Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD plus Depletion in Cancer Cells
Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD plus Depletion in Cancer Cells
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DOI：
10.1016/j.celrep.2018.11.043
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发表时间：
2018-12-11
期刊：
影响因子：
8.8
通讯作者：
Hall, Michael N.
中科院分区：
文献类型：
--
作者：
Benjamin, Don;Robay, Dimitri;Hall, Michael N.
高度糖酵解的癌细胞通过单羧酸转运蛋白1（MCT1）和4（MCT4）分泌糖酵解终产物乳酸盐和H+来防止细胞内酸化。我们报告说，syrosingopine，一种抗高血压药物，是一种双重的MCT1和MCT4抑制剂（具有60倍以上的效力MCT4），防止乳酸和H+外流。Syrosingopine与线粒体NADH脱氢酶抑制剂二甲双胍一起提高合成致死率。糖酵解的ATP生成步骤所需的NAD+通过线粒体NADH脱氢酶或乳酸脱氢酶从NADH再生。Syrosingopine治疗导致细胞内乳酸水平升高，从而最终产物抑制乳酸脱氢酶。由于二甲双胍和syrosingopine联合治疗导致NAD+再生能力丧失，导致糖酵解阻断，导致ATP耗竭和细胞死亡。因此，ATP水平可以通过外源性提供的NAD+、NAD前体烟酰胺单核苷酸（NMN）或维生素K2部分恢复。因此，药物抑制MCT 1和MCT 4联合二甲双胍治疗是一种潜在的癌症治疗方法。
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy.